Amoxicillin is a well-known broad spectrum penicillin type antibiotic used for the treatment of both gram positive and gram negative bacterial infections in animals and humans. Most commonly, amoxicillin occurs as its trihydrate and this form, amoxicillin trihydrate, is predominantly used in formulations. For the purpose of the present invention, the term ‘amoxicillin’ therefore refers to amoxicillin trihydrate.
Traditionally, amoxicillin is prepared from penicillin G or penicillin V following complex chemical conversions involving the intermediate formation of 6-amino penicillanic acid, see for example J. Verweij et al. (Recl. Trav. Chim. Pays-Bas (1993) 112, 66-81 and references cited therein). There are various drawbacks associated with this approach, the main ones being the fact that such processes require hazardous and environmentally harmful chemicals. Such chemicals, mostly solvents such as butyl acetate, dichloromethane, dimethyl acetamide, isopropanol and/or pyridine and auxiliary chemicals such as pivalic acid and triethyl amine, end up as unwanted contaminants in the final product. Levels of residual solvents and auxiliary chemicals in amoxicillin are often significant and values for individual contaminants ranging from 300 to 2000 ppm are not unusual. A well-known contaminant such as dichloromethane may often occur in ranges of from 1000 to 5000 ppm.
Fortunately, in the last two decades major improvements have been realized with the introduction of environmentally benign enzyme-catalyzed processes that are carried out in water such as described in A. Bruggink et al. (Org. Proc. Res. Dev. (1998) 2, 128-133 and references cited therein).
Consequently, the majority of β-lactam antibiotics nowadays rarely contain organic solvents or hazardous auxiliary chemicals other than perhaps minute traces (less than 300 ppm) of harmless low-carbon alcohols such as ethanol or methanol. The foregoing is certainly also true for amoxicillin.
In contrast with the many and significant disadvantages of organic contaminants stands one advantage, namely the fact that contaminants usually have a positive effect on the extent to, and the rate at, which the major component, for example amoxicillin, dissolves in aqueous environment. This advantage stemming from traditional chemical synthesis of antibiotics has disappeared with the introduction of enzymatic processes leading to β-lactam antibiotics of markedly improved purity. And today there remains a drawback of enzymatically produced β-lactam antibiotics such as amoxicillin that requires to be solved, namely decreased (speed of) solubility.